Regulation and Function of Epithelial Secreted Phospholipase A2 Group X in Asthma
Regulation and Function of Epithelial Secreted Phospholipase A2 Group X in Asthma
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DOI：
10.1164/rccm.201301-0084oc
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发表时间：
2013-07-01
影响因子：
24.7
通讯作者：
Gelb, Michael H.
中科院分区：
文献类型：
--
作者：
Hallstrand, Teal S.;Lai, Ying;Gelb, Michael H.
理论基础：间接气道高反应性(AHR)是哮喘的一个基本特征，表现为运动诱导的支气管收缩(EIB)。目的：探讨分泌型磷脂酶A(2)-X在哮喘小鼠气道上皮细胞和气道壁中的表达及其与AHR的关系，以及其在上皮细胞中的调节和功能。方法：对34例哮喘患者(19例有EIB，15例无EIB)和10例正常对照组进行了精确的表型分析，以检测哮喘患者气道上皮细胞基因表达、支气管内膜活检定量形态计量学和分泌蛋白水平的差异。在原代培养的呼吸道上皮细胞中检测SplA(2)-X基因(PLA2G10)表达的调节。应用PLA2(2)抑制剂和pl2g10缺失的小鼠气管上皮细胞，检测上皮Spla(2)-X在二十烷类化合物形成中的作用。测量和主要结果：我们发现哮喘患者呼吸道Spla(2)-X蛋白增加，上皮源性Spla(2)-X可能与间接AHR相关。Spla(2)-X在体外培养的哮喘上皮细胞分化过程中表达增加，受肿瘤坏死因子、IL-13、IL-17等炎症信号的调控，既由上皮细胞分泌，又直接参与上皮细胞释放花生四烯酸。结论：上皮源性Spla(2)-X与间接AHR在哮喘发病机制中有一定的关系，Spla(2)-X是炎性二十烷类物质形成的一种上皮调节因子。针对上皮性Spla(2)-X的治疗可能对哮喘有用。
Rationale: Indirect airway hyperresponsiveness (AHR) is a fundamental feature of asthma that is manifest as exercise-induced broncho-constriction (EIB). Secreted phospholipase A(2) group X (sPLA(2)-X) plays a key role in regulating eicosanoid formation and the development of inflammation and AHR in murine models.Objectives: We sought to examine sPLA(2)-X in the airway epithelium and airway wall of patients with asthma, the relationship to AHR in humans, and the regulation and function of sPLA(2)-X within the epithelium.Methods: We precisely phenotyped 34 patients with asthma (19 with and 15 without EIB) and 10 normal control subjects to examine in vivo differences in epithelial gene expression, quantitative morphometry of endobronchial biopsies, and levels of secreted protein. The regulation of sPLA(2)-X gene (PLA2G10) expression was examined in primary airway epithelial cell cultures. The function of epithelial sPLA(2)-X in eicosanoid formation was examined using PLA(2) inhibitors and murine tracheal epithelial cells with Pla2g10 deletion.Measurements and Main Results: We found that sPLA(2)-X protein is increased in the airways of patients with asthma and that epithelial-derived sPLA(2)-X may be increased in association with indirect AHR. The expression of sPLA(2)-X increases during in vitro epithelial differentiation; is regulated by inflammatory signals including tumor necrosis factor, IL-13, and IL-17; and is both secreted from the epitheliumand directly participates in the release of arachidonic acid by epithelial cells.Conclusions: These data reveal a relationship between epithelial-derived sPLA(2)-X and indirect AHR in asthma and that sPLA(2)-X serves as an epithelial regulator of inflammatory eicosanoid formation. Therapies targeting epithelial sPLA(2)-X may be useful in asthma.